Thitayanuwat P.Hengphasatporn K.Chankhamhaengdecha S.Shigeta Y.Mahidol University2025-06-252025-06-252025-01-01Journal of Physical Chemistry Letters (2025) , 6286-6292https://repository.li.mahidol.ac.th/handle/123456789/110920Porcine reproductive and respiratory syndrome virus (PRRSV) causes severe economic losses in the swine industry by targeting pulmonary alveolar macrophages via the CD163 receptor, particularly its SRCR5 domain. However, the molecular details of small-molecule inhibition at this interface remain unclear. Here, we provide the first mechanistic insights into how the PRRSV/CD163-IN-1 (B7) compound blocks CD163-SRCR5. Using structural refinement, molecular dynamics (MD) simulations, ensemble docking, and fragment molecular orbital (FMO) calculations, we identified a plausible B7/CD163-SRCR5 binding conformation. Due to the limitations of the crystal structure in representing conformational flexibility, we proposed an MD-refined model of CD163-SRCR5 to facilitate the efficient virtual screening of a small-molecule repurposing library. Baicalin emerged as a top candidate through the in silico analyses, consistent with previous experimental evidence. This result supports baicalin’s antiviral activity, reinforcing its potential as a lead compound. This study provides a molecular basis for ligand recognition at CD163-SRCR5 and a framework for designing PRRSV entry inhibitors.Materials ScienceChemistryArticleSCOPUS10.1021/acs.jpclett.5c015282-s2.0-10500837772919487185